Transdermal delivery of estrogens and progestins for providing contraception is a known concept (Sitruk-Ware, Transdermal application of steroid hormones for contraception, J Steroid Biochem Molecul Biol, Volume 53, p 247-2511). It is also known that estrogens and progestins do generally poorly penetrate the skin, for which reason it is common, to incorporate agents with skin penetrating enhancing effect in transdermal systems.
ORTHO EVRA® is the first transdermal contraceptive patch which received the approval from the Marketing Authorities. It was launched at first in the US in 2002. ORTHO EVRA® is a once-a-week transdermal contraceptive system with a size of 20 cm2 and comprises 6 mg Norelgestromin and 0.75 mg Ethinylestradiol.
ORTHO EVRA® is a thin, matrix-type transdermal contraceptive patch consisting of three layers. The backing layer is composed of a beige flexible film consisting of a low-density pigmented polyethylene outer layer and a polyester inner layer. It provides structural support and protects the middle adhesive layer from the environment. The middle layer contains polyisobutylene/polybutene adhesive, crospovidone, non-woven polyester fabric and lauryl lactate as inactive components. The active components in this layer are the hormones, Norelgestromin and Ethinylestradiol. The third layer is the release liner, which protects the adhesive layer during storage and is removed just prior to application. It is a transparent polyethylene terephthalate (PET) film with a polydimethylsiloxane coating on the side that is in contact with the middle adhesive layer.
AG200-15, the lead contraceptive patch developed by Agile Therapeutics, is currently under investigation in a Phase 3 study to evaluate the efficacy and safety. AG200-15 is designed to effectively deliver 25-30 μg estrogen (Ethinylestradiol) and 100-120 μg Levonorgestrel in a weekly regime for 21 days. The patch is applied once weekly for three weeks followed by a patch-free week.
A transdermal contraceptive patch comprising Gestodene in combination with an estrogen is not yet on the market.
However, there are a number of publications describing compositions for the transdermal delivery of Gestodene.
Gestodene itself is a known orally active synthetic progestin with a progesterone-like profile of activity (see, U.S. Pat. No. 4,081,537). It is used as an oral contraceptive in combination with certain estrogens.
U.S. Pat. No. 5,512,292 is directed to compositions comprising a contraceptive effective amount of Gestodene and an estrogen, such as Ethinylestradiol, together with a suitable permeation enhancer. The amount of the estrogen co-delivered is kept at a constant and contraceptive effective rate while the amount of Gestodene co-delivered varies depending on the phase of the menstrual cycle.
In U.S. Pat. No. 5,376,377 comparable studies between transdermal systems with and without penetration enhancers are shown. The studies include an adhesive layer made of ethylene vinyl acrylate and as the active ingredient, Gestodene and an estrogen (Ethinylestradiol). The study results indicate the need of incorporation of penetration enhancers in the adhesive layer so as to achieve contraceptive effective amounts. Maximal plasma levels of about 0.8 ng/mL were achieved.
WO 90/04397 also discloses examples of compositions for transdermal delivery of Gestodene, optionally in combination with an estrogen, such as Ethinylestradiol, wherein the composition further may comprise a penetration enhancer, such as 1,2-propandiol or isopropylmyristate. A number of various polymers are mentioned as adhesive layer. Examples on polar polymers (polyacrylates and silicones) in combination with a penetration enhancer are specifically disclosed. The resulting plasma levels of Gestodene at steady state conditions were approximately 250 to 337 pg/mL.
In U.S. Pat. No. 6,521,250 is disclosed an adhesive layer that comprises a mixture of styrene-isoprene block copolymer and a hydrogenated resin acid or its derivatives, the amount of the resin being of 55-92%. Such an adhesive layer seems suitable for the transdermal delivery of Estradiol in combination with a progestin in that such systems have a proper adhesive contact with the skin for long-term application and prevent crystallization of the hormones.
U.S. Pat. No. 5,904,931 relates to transdermal therapeutic systems containing in the drug-containing layer a steroid (such as Gestodene) and dimethyl isosorbide. The latter enhances the solubility of the steroid in the drug-containing layer. The concentration of the Gestodene in the drug-containing layer may vary from 1-40% by weight of the layer and the drug-containing layer may consist of adhesives such as polyacrylates, silicones, styrene-butadiene copolymers and polyisobutylenes. Especially, polar polymers such as polyacrylates, are suitable.
DE 199 06 152 relates to a transdermal drug delivery system in which Gestodene is embedded in a polar polymer, such as polyvinylpyrrolidone, methylcellulose, ethylcellulose, and hydroxypropylcellulose, previous to being added to an adhesive polymer, such as polyisobutylene. Thus, this transdermal drug delivery system is a two-phase system and the drug-containing layer is not transparent because of the content of the polar polymers, which upon exposure to water will result in the presence of milky-white spots. The amount of Gestodene in the drug-containing layer is 5.1% by weight of the drug-containing layer.
WO 02145701 describes a TTS (Transdermal Therapeutic System) which is suitable for steroids (Gestodene). Gestodene may be incorporated in the adhesive layer in an amount substantially at or near or even above the saturation with respect to their concentration in the carrier composition rather than substantially at subsaturation. Preferably, the amount of the steroid is from about 0.1% to about 6% by weight, based on the dry weight of the total carrier composition. The adhesive layer may include all non-toxic natural and synthetic polymers known and which are suitable for use in transdermal systems, for example polyacrylates, polysiloxanes, polyisobutylenes, styrene block copolymers and the like.
WO 92/07590 discloses compositions with penetration enhancers for the transdermal delivery of Gestodene and an estrogen so as to achieve maximal plasma levels of Gestodene of about 0.9 ng/mL. The amounts of the estrogen and of Gestodene are described that are present in the therapeutic device, and that are required to achieve a contraceptive effect, depend on many factors, such as the minimum necessary dosage of each drug; the permeability of the matrix, of the adhesive layer and of the rate-controlling membrane, if present; and the period of time for which the device will be fixed to the skin.
Since the drugs are to be released over a period of more than one day, there is, in fact, no upper limit to the maximum amounts of the drugs present in the device. The minimum amount of each drug is determined by the requirement that sufficient quantities of drug must be present in the device to maintain the desired rate of release over the given period of application.
Drug amounts or ranges of amounts are not mentioned in WO 92/07590.
So far the minimum amount of each drug, i.e. Gestodene and estrogen, to maintain the desired release rate over a defined period of administration is not clearly known.
EP 1 541 137 describes pharmaceutical compositions for transdermal delivery comprising a drug-containing layer that comprises Gestodene or an ester thereof and a carrier selected from the group consisting of polyisobutylenes, polybutenes, polyisoprenes, polystyrenes, styrene isoprene styrene block polymers, styrene butadiene styrene block polymers and mixtures thereof, wherein the drug-containing layer has a solubility for said Gestodene of no more than 3% by weight of the drug-containing layer, and wherein the Gestodene or an ester thereof is present in an amount ranging between 0.5 and 3% by weight of the drug-containing layer.
The Gestodene drug plasma levels after application of a composition which is a 10 cm2 patch comprising 0.9 mg Ethinylestradiol and 1.9 mg Gestodene is 2082 pg/mL (Cmax.) whereas a 10 cm2 patch comprising 0.67 mg Ethinylestradiol and 1.33 mg Gestodene reaches 1995 pg/mL (Cmax.) when applied as single dose.
EP 1 541 137 also demonstrates that a drug-containing layer of a polar polymer (polyacrylate) requires a concentration of Gestodene of 3.9% by weight of this layer to achieve the desired high release rate. Additionally, it is shown that the same high release rate can be achieved with a concentration of 1.9% by weight of Gestodene in a drug-containing layer comprising a less polar polymer, such as polyisobutylene.
Even EP 1 541 137 does not disclose the minimum amount of each drug, i.e. Gestodene and estrogen, to maintain the desired release rate over a defined period of administration.